The advantages of the use of a local treatment or administration when the active principle (AP) is in this way preferentially directed towards its site of action are known. It is proved, on the other hand, that oral or parenteral administration of a medicament and its systemic diffusion can, in certain cases, not give a satisfactory result. In addition, even in the case where a general or systemic treatment is aimed at, especially in the case of delayed-release formulations, it is of interest to insert the formulation into a suitable site.
Apart from the improvements in the local efficacy, the local treatment with respect to a general treatment above all allows the doses and the secondary effects, especially linked to the AP, to be decreased in the sites of the body where its presence is either useless or harmful.
The local administration of a medicament thus allows the therapeutic index of the product to be improved while decreasing, if need be, its general toxicity and the risk of systemic effects.
The cutaneous, ocular, naso-sinusal, pulmonary or even gastric or rectal topical forms were the first non-parenteral forms to use local administration. When the depot site of the formulation is accessible with relative difficulty or necessitates an invasive form and when the treatment must be repeated, or even more, chronic, even if the advantage of targeting is known, in practice its use comes up against the difficulty or even the discomfort of a repeated therapeutic action.
On the other hand, the advantages of the use of a sustained-release or delayed-release formulation which allows, in a single administration, the sick person to be given his/her medicament for several days, several weeks or several months, is known.
This delayed-release form improves compliance when the observance of the treatment does not depend on the sick person or the care personnel but on the preparation. This sustained-release in fact thus improves the comfort of the patient who is no longer constrained by his/her treatment and who thus continuously receives a regular and non-variable dose as a function of taking the medication.
The development of delayed-release forms has led the specialists to consider their local use, especially in the case mentioned above where the depot site is accessible with relative difficulty. The delayed-release form thus avoids having to repeat the administrations or, even more, surgery. In this way, it is possible to hope for significant local concentrations of medicament over a prolonged period without significant systemic doses, thus with fewer secondary effects. This solution is more particularly useful for products which are rapidly metabolized or have a short half-life when they are administered by the systemic route.
Inside the body, targeted and prolonged treatments such as intra- or peri-articular injections of delayed-released corticoids are thus envisaged. Cancers and especially solid tumours are candidates of choice for these local forms which allow the total injected doses of cytotoxic or antineoplastic compound to be decreased, whilst increasing the concentration in the tumour zone to be treated. This is thus capable of avoiding the serious secondary effects of this type of treatment.
Matrix Pharmaceutical proposes a delayed-release preparation based on collagen which will be able to be injected intra-tumorally (IntraDose CDDP-Cisplatin). This formulation is administered in cancers or cutaneous lesions with the aid of a 3 cc syringe and possibly a biopsy needle for the less accessible zones. In a viscous liquid volume which can reach 2 ml, it is thus limited to the initially relatively easy (peripheral) sites or to post-surgical treatments.
It is also possible to mention the MITSUI Patent (FR 2 497 661; JP 562 737) which describes a small rod or needle polylactide-polyglycolide (PLGA) form for local activity, allowing its direct implantation into a zone or an organ inside the body, and, for example, a tumour zone before or after exeresis.
The Gliadel form (Guildford) for its part describes a formulation based on polyanhydride in host form containing carmustine and which can, for example, be deposited at the time of surgery on a cerebral tumour (glioblastoma).
In the present state of medical technology, these targeted treatments inside the body are more often linked to serious surgical operations. They benefit from the prolonged effect of the formulation but cannot be easily repeated.
Chemo-embolization operations are also carried out which consist in injecting, into vessels, suspensions (microspheres), gels or glues with their solvent, which will be able to obstruct a nutrient vascular tract and liberate an AP in a tumour. The occlusion is obtained by deposition after the injection vehicle has left. This technique uses transluminal percutaneous angioplasty catheters to introduce the fluid into the vessel.
The local use of delayed-release forms is also envisaged in certain body cavities and in more accessible sites of the body.
The ®Ocusert system (Alza) is a flexible and oval ocular insert which forms a delayed-release reservoir device comprising an ethylene/vinyl acetate copolymer membrane and which can contain, for example, pilocarpine.
This device is placed in the conjunctival sac and liberates its product according to a zero-order profile. The delayed-release form allows the dose necessary for the same effect on the intraocular pressure to be decreased significantly. The therapeutic efficacy of pilocarpine in the treatment of glaucoma is thus 8 to 10 times better owing to the use of a delayed-release form compared with local drops.
American U.S. Pat. No. 3,545,439 whose contents are incorporated by reference describes an intra-vaginal delayed-release form formed of a ring made using a silicone elastomer and which liberates a medicament for several weeks.
In this case, the local delayed-release administration on the vaginal mucous membrane also allows, according to the AP, a general effect (contraception) to be obtained.
The medical device described by Bukh Meditee (International Patent Application PCT No. WO 89/03232 whose contents are incorporated by reference) allows the introduction into a body cavity of a matrix delayed-release form made of a substance which is poorly penetrable by water and containing an AP.
The delayed-release form combined with the device thus delivers the AP at the local level and during the period of the insertion of the said device. It describes, for example, a catheter for the urethra opening into the bladder combined with an antibiotic delayed-release form capable of preventing infections of the urinary tracts.
For large-volume liquid forms, certain existing processes of local injection could be used. Starting from intraurethral techniques, C. R. BARD, for example, has developed a formulation (Transurethral delivery Kit) which is a syringe containing a solution of collagen in glutaraldehyde which can be easily injected submucosally in volumes of 2.5 to 7.5 ml which form implants without active principle in the context of plastic surgery against incontinence.
The development of intraluminal vascular systems has led to the production of catheters allowing an AP to be liberated locally at their end. Contrary to the catheter which is simply open for liberating fluid, local administration can be obtained with a double-balloon or porous catheter with multiple perforations. This local solution, however, is limited by the time of insertion of the catheter. The pressure of the solution necessary to penetrate the wall also poses a tolerance problem.
For liquid solutions, a true local injection can be obtained in the wall with the aid of an injection system combined with a balloon (Interventional Technologies) or a catheter with a retractable needle (Bavarian Medical Technologies). The administration of the medicament, however, is not prolonged much with these immediate liquid forms.
A part of the device can sometimes be left locally and thus be associated with a delayed-release form. This is the case of the “stents” used, for example, in angioplasty to avoid restenosis, which can be covered by a layer containing an active principle, sometimes with a delayed-release effect. Two essential problems are then posed, the first is the suitability of the released medicament for the specific process of “coating”. The second is the limitation of the total dose by the space and the surface offered by the stent.
With heparin, for example, certain studies mention the significance of local treatment to avoid the systemic secondary effects. According to these studies, heparin inhibits the proliferation of smooth muscle cells after endothelial damage. Its systemic administration, in adjacent subcutaneous or local delayed-release form external to the vessel, always leads to a decrease in the neointimal proliferation but the local form is the only one not to involve systemic perturbations of coagulation.
It would even be possible to cite osmotic pumps which are used to validate prolonged local administrations with, as a major disadvantage, their surgical implantation. For this reason, they are not presently used in man.
All these examples indeed show the interest and the advantages brought by a targeted treatment, above all if it can be prolonged.
These technical solutions, however, all have certain disadvantages amongst which the most important are the lack of versatility of the solution retained, the association with a specific device which remains totally or partially inserted over the period of release of the medicament and, finally, the limits of the injectable volume, thus, of the dose of AP.
Each of these solutions allows only one or several particular cases in a well-defined site of the body to be treated.
Vectorization by local administration is sometimes described as first generation with respect to the “prodrug” and vector (liposomes . . . ) formulations called second generation or to macromolecular recognition systems or “site-specific” activation called third-generation. These solutions, even more than the present local administration techniques, however, are very specific, not always applicable and sometimes not very precise.
The aim of the invention is to propose a process solving the present major disadvantages of local administration or vectorization by flexible endoscopic surgical techniques (fibroscopy) or rigid endoscopic surgical techniques (endoscopy) and of interventional radiology (active or non-active catheter).
The non-dispersed solid and semi-solid formulations have the advantage of offering a minimal volume for a quantity of AP corresponding to a treatment dose. The solid and semi-solid delayed-release forms can thus allow several days of treatment in a volume of a few microlitres.
The local administration of a treatment allows the total therapeutic dose for the same effect to be decreased significantly.
The combination of a solid or semi-solid delayed-release form and of a local administration thus leads to the production of micro-dosages particularly adapted to local deposition at spaced intervals of time.
The present development of imaging, optical and micro-mechanical techniques applied to medicine in the field of intravascular or cavitary instrumentation and of minimally invasive surgery has led to the design of more and more fine and more and more precise tools allowing very deep local intervention in the body with minimal trauma and thus of multiplying the accessible sites.